Abstract:

Disclosed is
1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidi-
n-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one monohydrate, which has
strong antibacterial activity. The compound is highly safe and useful as
an original drug for pharmaceutical preparations. Also disclosed is a
method which is useful for producing
1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidi-
n-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one monohydrate.

9. The production method according to claim 3, wherein R3 is an
aralkyl group; R4 is an acyl group or an alkoxycarbonyl group.

Description:

TECHNICAL FIELD

[0001]The present invention relates to a novel naphthyridine derivative
monohydrate and a method for producing the same.

BACKGROUND ART

[0002]In medical practice, a wide variety of antibiotics and synthetic
antibacterial agents have been used for the treatment of infectious
diseases. However, resistant bacteria such as methicillin-resistant
Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE) and
penicillin-resistant Streptococcus pneumoniae (PRSP) have recently
emerged. The treatment of patients infected with such a resistant
organism has been a critical concern. In addition, multiresistant
organisms that acquired resistance to multiple drugs have emerged.
Infectious diseases caused by multiresistant organisms have been major
problems worldwide as intractable diseases.

[0003]The appearance of antimicrobial agents which are effective against
these resistant organisms has been strongly desired, and, for example, a
quinolone compound considered to be effective against MRSA is disclosed
in WO 99/07682 (PATENT DOCUMENT 1). Further, the compounds disclosed in
WO 2004/002490 (PATENT DOCUMENT 2) and WO 2004/002992 (PATENT DOCUMENT 3)
are known as the compounds having action mechanisms different from those
of the existing drugs.

[0004]There is a demand for the development of a drug having high safety
and strong antibacterial activities against gram-positive bacteria,
gram-negative bacteria and resistant bacteria. Further, a useful method
for producing this drug and a useful production intermediate have been
awaited with great expectations.

Means for Solving the Problems

[0005]Under such circumstances, the present inventors conducted extensive
studies and found that
1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidi-
n-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one monohydrate (1) has
strong antibacterial activity and high safety, (2) does not exhibit
deliquescence or hygroscopicity, (3) is easy to handle, (4) is produced
using a solvent which is safe to human body, (5) is produced under
conditions with a little environmental burden, and (6) can be mass
produced.

[0006]Further, the inventors found that
1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidi-
n-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one monohydrate can be
produced easily by reacting

(1) a naphthyridine derivative represented by the formula [7]

##STR00001##

and produced by reacting a pyridine derivative represented by the formula
[1]

##STR00002##

with an acrylic acid ester to give an acrylic acid derivative represented
by the general formula [2]

##STR00003##

[0007]wherein R1 represents an alkyl group,

then reducing/cyclizing the obtained acrylic acid derivative to give a
dihydronaphthyridine derivative represented by the formula [3]

##STR00004##

then reacting the obtained dihydronaphthyridine derivative with a compound
represented by the general formula [4]

##STR00005##

[0008]wherein L1 represents a leaving group; Y represents a protected
carbonyl group, to give a dihydronaphthyridine derivative represented by
the general formula [5]

##STR00006##

[0009]wherein Y is defined as above,

then oxidizing the obtained dihydronaphthyridine derivative to give a
naphthyridine derivative represented by the general formula [6]

##STR00007##

[0010]wherein Y is defined as above, and

then deprotecting the obtained naphthyridine derivative with(2) a
piperidine derivative represented by the general formula [17]

##STR00008##

[0011]wherein R4 represents an imino protecting group

and produced by reacting a kojic acid derivative represented by the
general formula [8]

to give a kojic acid derivative represented by the general formula [10]

##STR00011##

[0014]wherein R2 and X are defined as above,

then deprotecting the obtained kojic acid derivative to give a kojic acid
derivative represented by the general formula [11]

##STR00012##

[0015]wherein X is defined as above,

then reacting the obtained kojic acid derivative with ammonia to give a
pyridine derivative represented by the formula [12]

##STR00013##

then oxidizing the obtained pyridine derivative to give a pyridine
derivative represented by the formula [13]

##STR00014##

then reacting the obtained pyridine derivative with a piperidine
derivative represented by the general formula [14]

##STR00015##

[0016]wherein R3 represents an imino protecting group,

to give a piperidine derivative represented by the general formula [15]

##STR00016##

[0017]wherein R3 is defined as above,

then protecting the imino group to give a piperidine derivative
represented by the general formula [16]

##STR00017##

[0018]wherein R4 is defined as above; R3 is defined as above,

and then deprotecting the obtained piperidine derivative to give(3) a
naphthyridine derivative represented by the general formula [18]

##STR00018##

[0019]wherein R4 is defined as above,

and then deprotecting the obtained naphthyridine derivative.

[0020]The inventors further found that a kojic acid derivative represented
by the general formula [19]

##STR00019##

[0021]wherein R2a represents a hydrogen atom or a hydroxyl protecting
group; X represents a leaving group

is an important production intermediate.

ADVANTAGES OF THE INVENTION

[0022]1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)pip-
eridin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one monohydrate of the
present invention (1) has strong antibacterial activity and high safety,
(2) does not exhibit deliquescence or hygroscopicity, (3) is easy to
handle, (4) is produced using a solvent which is safe to human body, (5)
is produced under conditions with a little environmental burden and (6)
can be mass produced, and is hence useful as a bulk pharmaceutical.

[0023]The production method of the present invention has features such as
(1) high yield, (2) no silica gel column chromatography required, (3)
consequently little waste product and (4) no toxic or unstable reagent
used, and is hence useful to produce
1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidi-
n-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one monohydrate.

[0024]Further, the kojic acid derivative represented by the general
formula [19]

##STR00020##

wherein R2a and X are defined as aboveis a useful production
intermediate.

BEST MODE FOR CARRYING OUT THE INVENTION

[0025]Hereinafter, the present invention will be described in detail.

[0026]In the present specification, unless otherwise specified, a halogen
atom refers to, for example, a fluorine atom, a chlorine atom, a bromine
atom and an iodine atom. An alkyl group refers to, for example, a
straight-chain or branched-chain C1-6 alkyl group such as methyl,
ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl and
pentyl. An aralkyl group refers to, for example, an ar-C1-6 alkyl
group such as benzyl, diphenylmethyl, trityl, phenethyl and
naphthylmethyl. An alkoxy alkyl group refers to, for example, a C1-6
alkyloxy C1-6 alkyl group such as methoxymethyl and 1-ethoxyethyl.
An aralkyloxyalkyl group refers to, for example, an ar-C1-6 alkyloxy
C1-6 alkyl group such as benzyloxymethyl and phenethyloxymethyl. An
alkylsulfonyl group refers to, for example, a C1-6 alkylsulfonyl
group such as methylsulfonyl, trifluoromethylsulfonyl and ethylsulfonyl.
An arylsulfonyl group refers to, for example, a group such as
benzenesulfonyl and toluenesulfonyl. An alkylsulfonyloxy group refers to,
for example, a C1-6 alkylsulfonyloxy group such as
methylsulfonyloxy, trifluoromethylsulfonyloxy and ethylsulfonyloxy. An
arylsulfonyloxy group refers to, for example, a group such as
benzenesulfonyloxy and toluenesulfonyloxy.

[0027]An acyl group refers to, for example, a formyl group, a
straight-chain or branched-chain C2-6 alkanoyl group such as acetyl,
propionyl, butyryl, isovaleryl and pivaloyl, an ar C1-6
alkylcarbonyl group such as benzylcarbonyl, a cyclic hydrocarbon carbonyl
group such as benzoyl and naphthoyl, and a heterocyclic carbonyl group
such as nicotinoyl, thenoyl, pyrrolizinocarbonyl and furoyl. An
alkoxycarbonyl group refers to, for example, a straight-chain or
branched-chain C1-6 alkyloxycarbonyl group such as methoxycarbonyl,
ethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl,
2-ethylhexyloxycarbonyl, tert-butoxycarbonyl and tert-pentyloxycarbonyl.
An aralkyloxycarbonyl group refers to, for example, an ar C1-6
alkyloxycarbonyl group such as benzyloxycarbonyl and
phenethyloxycarbonyl.

[0028]An oxygen-containing heterocyclic group refers to, for example, a
group such as tetrahydropyranyl and tetrahydrofuranyl. A
sulfur-containing heterocyclic group refers to, for example, a group such
as tetrahydrothiopyranyl. A protected carbonyl group refers to, for
example, a group formed from a carbonyl group and an alcohol, such as
(hydroxy)(methoxy)methylene, (hydroxy)(ethoxy)methylene,
(hydroxy)(propoxy)methylene, (hydroxy)(isopropoxy)methylene,
(hydroxy)(butoxy)methylene, (hydroxy)(pentyloxy)methylene,
(hydroxy)(hexyloxy)methylene, (hydroxy)(heptyloxy)methylene,
(hydroxy)(octyloxy)methylene, (hydroxy)(1,1-dimethylpropoxy)methylene,
dimethoxymethylene, diethoxymethylene, dipropoxymethylene,
diisopropoxymethylene, dibutoxymethylene, bis(benzyloxy)methylene,
1,3-dioxolan-2-ylidene and 1,3-dioxan-2-ylidene, a group formed from a
carbonyl group and a thiol, such as bis(methylthio)methylene,
bis(ethylthio)methylene, bis(benzylthio)methylene,
1,3-dithiolan-2-ylidene and 1,3-dithian-2-ylidene, and a group such as
oxazolin-2-ylidene, imidazolidin-2-ylidene and thiazolidin-2-ylidene. A
leaving group refers to, for example, a halogen atom, an alkylsulfonyloxy
group and an arylsulfonyloxy group.

[0029]A hydroxyl protecting group encompasses all groups which are usable
as a usual hydroxyl protecting group, and examples include groups
described in "Greene's Protective Groups in Organic Synthesis" by M. Wuts
and W. Greene, 4th edition, John Wiley & Sons, INC., 2006, p. 16 to 366.
Specific examples include an acyl group, an alkoxycarbonyl group, an
aralkyloxycarbonyl group, an alkyl group, an aralkyl group, an
oxygen-containing heterocyclic group, a sulfur-containing heterocyclic
group, an alkoxyalkyl group, an aralkyloxyalkyl group, an alkylsulfonyl
group, and an arylsulfonyl group.

[0030]An imino protecting group encompasses all groups which are usable as
a usual imino protecting group, and examples include groups described in
"Greene's Protective Groups in Organic Synthesis" by M. Wuts and W.
Greene, 4th edition, John Wiley & Sons, INC., 2006, p. 696 to 926.
Specific examples include an acyl group, an alkoxycarbonyl group, an
aralkyloxycarbonyl group, an aralkyl group, an alkylsulfonyl group, and
an arylsulfonyl group.

[0031]Preferable
1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidi-
n-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one monohydrates used in the
present invention are the following compounds.

[0032]The crystals of the
1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidi-
n-1-yl)ethyl-7-fluoro-1,5-naphthyridin-2(1H)-one monohydrate having the
diffraction angles 2θ of 6.8°, 8.2°, 14.2° and
15.7° in the powder X-ray diffraction pattern are preferable.

[0033]In addition, characteristic peaks of powder X-ray diffraction may
vary depending on measurement conditions. For this reason, the peak in
the powder x-ray diffraction of the compound of the present invention
should not be strictly interpreted.

[0034]In the present invention, preferable production methods include the
following methods.

[0035]The production method wherein R1 is an ethyl group, a propyl
group or a butyl group is preferable, with the production method wherein
R1 is a butyl group being more preferable.

[0036]The production method wherein R2 is an acyl group, an aralkyl
group or an oxygen-containing heterocyclic group is preferable, with the
production method wherein R2 is an oxygen-containing heterocyclic
group being more preferable, and with the production method wherein
R2 is a tetrahydropyranyl group being further preferable.

[0037]The production method wherein R3 is an acyl group, an
alkoxycarbonyl group or an aralkyl group is preferable, with the
production method wherein R3 is an aralkyl group being more
preferable, and with the production method wherein R3 is a benzyl
group being further preferable.

[0038]The production method wherein R4 is an acyl group, an
alkoxycarbonyl group or an aralkyl group is preferable, with the
production method wherein R4 is an acyl group or an alkoxycarbonyl
group being more preferable, and with the production method wherein
R4 is an alkoxycarbonyl group being further preferable.

[0039]The production method wherein X is a chloride atom is preferable.

[0040]The production method wherein Y is a dimethoxymethylene group, a
diethoxymethylene group, a dipropoxymethylene group, a
1,3-dioxolan-2-ylidene group or a 1,3-dioxan-2-ylidene group is
preferable, with the production method wherein Y is a dimethoxymethylene
group, a diethoxymethylene group or a 1,3-dioxolan-2-ylidene group being
more preferable, and with the production method wherein Y is a
dimethoxymethylene group being further preferable.

[0041]In the compound represented by the general formula [19], preferable
compounds include the following compounds.

[0042]The compound wherein R2a is a hydrogen atom, an acyl group, an
aralkyl group or an oxygen-containing heterocyclic group is preferable,
with the compound wherein R2a is a hydrogen atom or an
oxygen-containing heterocyclic group being more preferable, with the
compound wherein R2a is a hydrogen atom or a tetrahydropyranyl group
being further preferable, and with the compound wherein R2a is a
hydrogen atom being the most preferable.

[0043]The production method of the present invention is hereinafter
described.

##STR00021##

wherein R1 is defined as above.(1-1)

[0044]The compound of the general formula [2] can be produced by reacting
the compound of the formula [1] with an acrylic acid ester in the
presence of a catalyst, in the presence or absence of a base, and in the
presence or absence of a ligand. The reaction may be carried out, for
example, by the method described in "Chem. Rev." by I. P. Beletskaya and
A. V. Cheprakov, 2000, Vol. 100, p. 3009 to 3066, or by any method in
accordance therewith.

(1-2)

[0045]The compound of the formula [3] can be produced by
reducing/cyclizing the compound of the general formula [2] in the
presence of a catalyst.

[0046]The reduction reaction may be carried out, for example, by the
method described in "Comprehensive Organic Transformations" by Richard C.
Larock, VCH Publishers, INC., 1989, p. 6 to 17, or any method in
accordance therewith.

[0047]The solvent used in the reduction reaction may be any solvent
insofar as it does not affect the reaction, and examples include alcohols
such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; aromatic
hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane,
tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene
glycol dimethyl ether, diethylene glycol diethyl ether, dibutyl ether and
ethylene glycol monomethyl ether; sulfoxides such as dimethyl sulfoxide,
esters such as ethyl acetate and butyl acetate; amides such as
N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidone;
ketones such as acetone and 2-butanone as well as water, and these
solvents may be used in mixture. Preferable examples of the solvent are
methanol and ethanol.

[0050]The amount of the catalyst used may be 0.001 to 5 times weight,
preferably 0.01 to 0.5 times weight, with respect to the compound of the
general formula [2].

[0051]The amount of the reducing agent may be 1 to 100 times by mole,
preferably 1 to 5 times by mole, with respect to the compound of the
general formula [2].

[0052]The reduction reaction may be carried out at -30 to 150° C.,
preferably 0 to 100° C., for 30 minutes to 120 hours.

[0053]The solvent used in the cyclization reaction may be any solvent
insofar as it does not affect the reaction, and examples include alcohols
such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; aromatic
hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane,
tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene
glycol dimethyl ether, diethylene glycol diethyl ether, dibutyl ether and
ethylene glycol monomethyl ether; sulfoxides such as dimethyl sulfoxide;
esters such as ethyl acetate and butyl acetate; amides such as
N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidone;
ketones such as acetone and 2-butanone as well as water, and these
solvents may be used in mixture. Preferable solvents include toluene and
xylene.

[0054]The cyclization reaction may be carried out at 0 to 200° C.,
preferably 50 to 130° C., for 30 minutes to 120 hours.

(1-3)

[0055]The compound of the formula [3] can be produced by reacting the
compound of the formula [1] with an acrylic acid ester in the presence of
a catalyst, in the presence or absence of a base, in the presence or
absence of a ligand; and in the presence of a reducing agent. The
reaction is a one-pot reaction to produce the compound of the formula
[3]. The reaction may be carried out in accordance with the production
method (1-1) and the production method (1-2).

##STR00022##

wherein L1 and Y are defined as above.(2-1)

[0056]Known compounds of the general formula [4] are, for example,
2-(2-bromomethyl)-1,3-dioxolane, 2-bromo-1,1-diethoxyethane and
2-bromo-1,1-dimethoxyethane.

[0057]The compound of the general formula [5] can be produced by reacting
the compound of the general formula [4] with the compound of the formula
[3] in the presence of a base.

[0058]The solvent used in this reaction may be any solvent insofar as it
does not affect the reaction, and examples include amides such as
N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidone;
halogenated hydrocarbons such as methylene chloride, chloroform and
dichloroethane; aromatic hydrocarbons such as benzene, toluene and
xylene; ethers such as dioxane, tetrahydrofuran, anisole, ethylene glycol
dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol
diethyl ether and ethylene glycol monomethyl ether, sulfoxides such
dimethyl sulfoxide; esters such as ethyl acetate as well as water, and
these solvents may be used in mixture. Preferable solvents are
N,N-dimethylacetamide and dimethyl sulfoxide.

[0060]The amounts of the base and the general formula [4] compound used
may be 1 to 50 times by mole, preferably 1 to 5 times by mole, with
respect to the compound of the formula [3].

[0061]The reaction may be carried out at -30 to 150° C., preferably
0 to 100° C., for 30 minutes to 48 hours.

(2-2)

[0062]The compound of the general formula [6] can be produced by oxidizing
the compound of the general formula [5] in the presence or absence of a
radical initiator, in the presence or absence of a base. The reaction may
be carried out, for example, by the methods described in Chem. Rev., by
Djerassi C., p. 271 to 317, Vol. 43, 1948 and "Bioorg. Med. Chem. Lett.",
by Julianne A. Hunt, 2003, Vol. 13, p. 467 to 470, or by any method in
accordance therewith.

[0063]The solvent used in this reaction may be any solvent insofar as it
does not affect the reaction, and examples include amides such as
N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidone;
halogenated hydrocarbons such as methylene chloride, chloroform and
dichloroethane; aromatic hydrocarbons such as benzene and chlorobenzene;
ethers such as dioxane, tetrahydrofuran, anisole, ethylene glycol
dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol
diethyl ether and ethylene glycol monomethyl ether; sulfoxides such as
dimethyl sulfoxide as well as esters such as ethyl acetate, and these
solvents may be used in mixture. A preferable solvent is chlorobenzene.

[0067]The amount of the oxidizing agent used is 1 to 30 times by mole,
preferably 1 to 5 times by mole, with respect to the compound of the
formula [5].

[0068]The amount of the radical initiator used as necessary is 0.0001 to
0.5 times by mole, preferably 0.001 to 0.1 times by mole, with respect to
the compound of the formula [5].

[0069]The reaction may be carried out at -30 to 150° C., preferably
0 to 100° C., for 30 minutes to 48 hours.

[0070]The compound of the general formula [6] is, for example,
1-(2,2-diethoxyethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one.
1-(2,2-Diethoxyethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one can be produced
by reacting 7-fluoro-1,5-naphthyridin-2(1H)-one with
2-bromo-1,1-diethoxyethane.

[0071]The reaction may be carried out by the method described in WO
2007/138974 or by any method in accordance therewith.

(2-3)

[0072]The compound of the formula [7] can be produced by deprotecting the
compound of the general formula [6]. The reaction may be carried out, for
example, by the method described in "Greene's Protective Groups in
Organic Synthesis" by M. Wuts and W. Greene, 4th edition, John Wiley &
Sons, INC., 2006, p. 435 to 505 or by any method in accordance therewith.

##STR00023##

wherein R2, R3, R4, L2 and X are defined as above.

[0073]The compound of the general formula [8] can be produced from kojic
acid.

(3-1)

[0074]Known compounds of the general formula [9] include, for example,
1-bromo-2-chloroethane and 1,2-dibromoethane.

[0075]The compound of the general formula [10] can be produced by reacting
the compound of the general formula [9] with the compound of the general
formula [8] in the presence of a base.

[0076]The reaction may be carried out in accordance with Production Method
2-1.

(3-2)

[0077]The compound of the general formula [11] can be produced by
deprotecting the compound of the general formula [10]. The reaction may
be carried out, for example, by the method described in "Greene's
Protective Groups in Organic Synthesis" by M. Wuts and W. Greene, 4th
edition, John Wiley & Sons, INC., 2006, p. 16 to 366 or by any method in
accordance therewith.

[0078]Further, the compound of the general formula [11] can be produced by
reacting the compound of the general formula [9] with kojic acid. The
reaction may be carried out in accordance with Production Method 3-1.

(3-3)

[0079]The compound of the formula [12] can be produced by reacting the
compound of the general formula [11] with ammonia.

[0080]The solvent used in this reaction may be any solvent insofar as it
does not affect the reaction, and examples include alcohols such as
methanol, ethanol, 2-propanol and 2-methyl-2-propanol; aromatic
hydrocarbons such as benzene, toluene, and xylene; ethers such as
dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether,
diethylene glycol dimethyl ether, diethylene glycol diethyl ether and
ethylene glycol monomethyl ether; sulfoxides such as dimethyl sulfoxide;
esters such as ethyl acetate; amides such as N,N-dimethylformamide,
N,N-dimethylacetamide and 1-methyl-2-pyrrolidone as well as water, and
these solvents may be used in mixture. A preferable solvent includes
water.

[0081]The ammonia used in this reaction includes ammonia water and so on.
The amount of the ammonia used may be 1 to 100 times by mole, preferably
1 to 30 times by mole, with respect to the compound of the general
formula [11].

[0082]The reaction may be carried out at room temperature to 150°
C., preferably 50 to 100° C., for 30 minutes to 120 hours.

(3-4)

[0083]The compound of the formula [13] can be produced by oxidizing the
compound of the formula [12]. The reaction may be carried out by the
methods described in "Advanced Organic Chemistry", by Jerry March, the
4th edition, John Wiley & Sons, INC., 1992, p. 1167 to 1171 and
"Comprehensive Organic Transformations" by Richard C. Larock, VCH
Publishers, INC., 1989, p. 604 to 614 or any method in accordance
therewith.

[0084]The solvent used in the reaction may be any solvent insofar as it
does not affect the reaction, and examples include halogenated
hydrocarbons such as methylene chloride, chloroform and dichloroethane;
ethers such as dioxane, tetrahydrofuran, anisole, ethylene glycol
dimethyl ether, diethylene glycol dimethyl ether, diethylene glycol
diethyl ether and ethylene glycol monomethyl ether; sulfoxides such as
dimethyl sulfoxide; esters such as ethyl acetate; amides such as
N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidone;
acids such as acetic acid as well as water, and these solvents may be
used in mixture. A preferable solvent includes tetrahydrofuran.

[0086]The amount of the oxidizing agent used in the reaction is 1 to 30
times by mole, preferably 1 to 5 times by mole, with respect to the
compound of the formula [12].

[0087]The reaction may be carried out at -78 to 200° C., preferably
0 to 100° C., for 30 minutes to 48 hours.

(3-5)

[0088]The compound of the general formula [15] can be produced by reacting
the compound of the general formula [14] with the compound of the formula
[13] in the presence of a reducing agent. The reaction may be carried out
by the methods described in WO 02/50061, WO 02/56882, "Advanced Organic
Chemistry", by Jerry March, the 4th edition, John Wiley & Sons, INC.,
1992, p. 898 to 900 and "Comprehensive Organic Transformations" by
Richard C. Larock, VCH Publishers, INC., 1989, p. 421 to 425 or any
method in accordance therewith.

[0089]The solvent used in the reaction may be any solvent insofar as it
does not affect the reaction, and examples include alcohols such as
methanol, ethanol, 2-propanol and 2-methyl-2-propanol; halogenated
hydrocarbons such as methylene chloride, chloroform and dichloroethane;
aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such
as dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether,
diethylene glycol dimethyl ether, diethylene glycol diethyl ether and
ethylene glycol monomethyl ether; sulfoxides such as dimethyl sulfoxide;
esters such as ethyl acetate; amides such as N,N-dimethylformamide,
N,N-dimethylacetamide and 1-methyl-2-pyrrolidone as well as water, and
these solvents may be used in mixture. A preferable solvent includes
methanol.

[0090]The reducing agent used in this reaction includes, for example,
hydride complexes such as lithium aluminum hydride, sodium
triacetoxyborohydride, sodium cyanoborohydride and sodium borohydride,
borane, sodium as well as sodium amalgam. Alternatively, electrolytic
reduction which uses copper or platinum for the cathode; catalytic
reduction which uses Raney nickel, platinum oxide or palladium black as
well as the reduction which uses "zinc/acid" may also be used. A
preferable reducing agent includes sodium borohydride. Sodium borohydride
can be used in the form of solid or solution.

[0091]The amounts of the compound of the general formula [14] and the
reducing agent used in the reaction are 1 to 50 times by mole, preferably
1 to 5 times by mole, with respect to the compound of the formula [13].

[0092]The reaction may be carried out at -30 to 150° C., preferably
0 to 100° C., for 10 minutes to 120 hours.

(3-6)

[0093]The compound of the general formula [16] can be produced by
protecting the imino group of the compound of the general formula [15].
The reaction may be carried out, for example, by the method described in
"Greene's Protective Groups in Organic Synthesis" by M. Wuts and W.
Greene, 4th edition, John Wiley & Sons, INC., 2006, p. 696 to 926 or any
method in accordance therewith.

(3-7)

[0094]The compound of the general formula [17] can be produced by
deprotecting the compound of the general formula [16]. The reaction may
be carried out, for example, by the method described in "Greene's
Protective Groups in Organic Synthesis" by M. Wuts and W. Greene, 4th
edition, John Wiley & Sons, INC., 2006, p. 696 to 926 or any method in
accordance therewith.

##STR00024##

wherein R4 is defined as above.(4-1)

[0095]The compound of the general formula [18] can be produced by reacting
the compound of the general formula [17] with the compound of the formula
[7]. The reaction may be carried out in accordance with Production Method
3-5.

(4-2)

[0096]The compound of the formula [20] can be produced by deprotecting the
compound of the general formula [18], followed by neutralization
crystallization. The deprotection reaction may be carried out, for
example, by the method described in "Greene's Protective Groups in
Organic Synthesis" by M. Wuts and W. Greene, 4th edition, John Wiley &
Sons, INC., 2006, p. 696 to 926 or any method in accordance therewith.

[0097]The solvent used in this reaction may be any solvent insofar as it
does not adversely affect the reaction, and examples include mixed
solvents of water and organic solvents as well as water.

[0098]The organic solvent includes, for example, alcohols such as
methanol, ethanol, 2-propanol and 2-methyl-2-propanol; halogenated
hydrocarbons such as methylene chloride, chloroform and dichloroethane;
aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such
as dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether,
diethylene glycol dimethyl ether, diethylene glycol diethyl ether and
ethylene glycol monomethyl ether; sulfoxides such as a dimethyl
sulfoxide, esters such as ethyl acetate; ketones such as acetone and
2-butanone; amides such as N,N-dimethylformamide, N,N-dimethylacetamide
and 1-methyl-2-pyrrolidone; and these solvents may be used in mixture.

[0099]Preferable solvents include mixed solvents of water and alcohols as
well as water, with water being more preferable.

[0100]When mixed solvents of water and an organic solvent(s) are used, the
ratio of water to an organic solvent(s) (water/organic solvent) is within
the range of preferably 100/0 to 50/50, more preferably 100/0 to 80/10.

[0101]The reaction may be carried out at -20 to 120° C., preferably
10 to 80° C., for 10 minutes to 120 hours.

[0102]The production method of the present invention has features such as
(1) high yield, (2) no silica gel column chromatography required, (3)
consequently little waste is produced and (4) no toxic or unstable
reagent used, and is hence useful as an industrial production method.

[0103]In Production Methods 1 to 4, the compounds of the formulae [3],
[7], [12] and as well as the compounds of the general formulae [2], [5],
[6], [8], [10], [11], [15], [16], [17] and [18] can be isolated and
purified, but may be used for the following reaction without being
isolated.

[0104]When the compound of the present invention represented by the
formula [20] is used as a pharmaceutical product, pharmaceutical adjuncts
routinely used for the drug formulation such as an excipient, a carrier
and a diluent may be mixed as necessary. These can be administered orally
or parenterally in accordance with a routine manner in the dosage form of
tablets, capsules, powders, syrups, granules, pills, suspensions,
emulsions, liquids/solutions, particulate preparations, suppositories,
ophthalmic solutions, nasal drops, ear drops, patches, ointments or
injections. The route, dosage and frequency of the administration can be
suitably selected according to the age, weight and symptoms of a patient.
The compound as a pharmaceutical product may typically be administered
orally or parenterally (e.g., administration by injection, intravenous
drip or to a rectum site) in a dose of 0.01 to 1000 mg/kg to an adult at
one to several times a day.

[0107]The compound of the present invention represented by the formula
[20] exhibits good safety. The safety is evaluated by a wide variety of
tests, which are selected from various safety tests including, for
example, a cytotoxicity test, a selectivity test targeting to DNA gyrase
in human and organisms, a selectivity test targeting to topoisomerase IV
in human and organisms, hERG test, repeated-dose toxicity study,
cytochrome P450 (CYP) activity inhibition test, metabolism dependent
inhibition test, in vivo mouse micronucleus assay and in vivo rat liver
USD assay.

[0108]The compound of the present invention represented by the formula
[20] has good metabolic stability. The metabolic stability is evaluated
by a wide variety of tests, which are selected from various stability
tests including, for example, human liver microsome metabolic stability
assay and human S9 metabolic stability assay.

[0109]Hereinafter, the usefulness of the compound of the present invention
represented by the formula [20] is described with reference to the
following Test Examples.

Test Example 1

Susceptibility Test

[0110]The compound of Example 16 was selected as the compound of the
present invention.

[0111]The compound of the present invention was dissolved in dimethyl
sulfoxide and measured for the antibacterial activity (MIC) by a
microtiter broth dilution method recommended by Japanese Society of
Chemotherapy.

[0113]The bacterial cells, grown overnight on a Mueller-Hinton agar: MHA
plate at 35° C., were suspended in a sterilized physiological
saline so as to be a 0.5 McFarland equivalent standard. The cell
suspension was diluted ten-fold to prepare an inoculum. Approximately
0.005 mL of the inoculum was inoculated into a cation-adjusted
Mueller-Hinton broth (CAMHB), 100 μL/well containing the test
substance and allowed to grow overnight at 35° C. The lowest
concentration of the test substance at which no bacterial growth was
observed by the naked eye was determined as MIC.

[0115]The compound of the present invention demonstrated good
antibacterial activities against various bacterial strains.

Test Example 2

Hygroscopicity Test

[0116]The compound of Example 16 was selected as the compound of the
present invention. The compound of Comparative Example 1 was selected as
the comparative compound.

[0117]The compound of the present invention and the comparative compound
were stored for three weeks under the conditions of room temperature and
the relative humidity of 97%. As a result, the compound of the present
invention was powder with no apparent change. On the other hand, the
comparative compound had deliquesced.

[0118]The compound of the present invention exhibited high stability.

Test Example 3

Solubility

[0119]The compound of Example 16 was selected as the compound of the
present invention.

[0120]The compound of the present invention was added in an excessive
amount to a 0.2 mol/L phosphate buffer solution (pH 6.5), and the mixture
was shaken for 48 hours in a thermostatic shaker (25° C.), and
centrifuged, and the supernatant thereof was filtered through a filter
having a pore size of 0.45 μm, whereby the solubility was measured by
high speed liquid chromatography. As a result, the solubility to the 0.2
mol/L phosphate buffer solution (pH 6.5) was 21.2 mg/mL.

EXAMPLE

[0121]The present invention is described in reference to the following
examples, but is not limited thereto.

[0125]To a solution of 0.11 kg of sodium hydroxide in 1000 mL of water,
1.4 kg of a 12% sodium hypochlorite aqueous solution and 0.40 kg of
2-chloro-5-fluoronicotinamide were added, and the mixture was stirred for
2 hours and 30 minutes at room temperature. The reaction mixture was
heated to 45° C. and stirred for 4 hours. The reaction mixture was
cooled to room temperature, ethyl acetate and 6 mol/L hydrochloric acid
were added thereto. The organic layer was separated and the aqueous layer
was extracted with ethyl acetate. The organic layer and the extract were
combined, anhydrous magnesium sulfate and activated carbon were added
thereto, and the mixture was stirred for 30 minutes at room temperature.
Insoluble matter was filtered out and the solvent was evaporated under
reduced pressure to give 0.29 kg of 2-chloro-5-fluoropyridin-3-amine as a
brown solid.

[0128]To a suspension of 25.0 g of 2-chloro-5-fluoropyridin-3-amine, 3.8 g
of bis(tricyclohexyl phosphine)palladium (II) chloride and 1.5 g of
2-(di-tert-butylphosphino)biphenyl in 75 mL of butyl acrylate, 44.1 g of
diisopropylethylamine was added, 15.7 g of formic acid was added dropwise
thereto at room temperature, and the mixture was refluxed for 3 hours. To
the reaction mixture, 32.1 g of diisopropylethylamine and 11.5 g of
formic acid were added at 100° C., and the mixture was refluxed
for 5 hours. The reaction mixture was cooled to 80° C., 50 mL of
toluene and 75 mL of water were added thereto and the resultant mixture
was cooled to room temperature. The solid product was obtained by
filtration, and washed using in the order of toluene and water to give
18.0 g of 7-fluoro-3,4-dihydro-1,5-naphthyridin-2(1H)-one as a white
solid.

[0132]A mixed solution of 150 mL of butyl acetate and 73 mL of butyl
acrylate was refluxed with heating for 45 minutes under a nitrogen
atmosphere. The reaction mixture was cooled to 30° C., 50.0 g of
2-chloro-5-fluoropyridine-3-amine, 3.8 g of palladium (II) acetate, 44.8
g of triphenylphosphine and 36.6 g of sodium carbonate were added
thereto, and the mixture was refluxed for 13 hours under a nitrogen
atmosphere. The reaction mixture was cooled to room temperature, 150 mL
of water and 700 mL of butyl acetate were added thereto, and the mixture
was stirred for 1 hour. Insoluble matter was filtered out, and the filter
residue was washed using 50 mL of butyl acetate. The filtrate and the
wash liquid were combined, the organic layer was separated, and 800 mL of
the solvent was evaporated under reduced pressure. To the obtained
residue, 300 mL of cyclohexane and 30 mL of toluene were added dropwise,
the mixture was cooled to 5° C., and the solid product was
obtained by filtration and washed using a mixed solution of
toluene-cyclohexane (1:2) and toluene to give 57.8 g of butyl
(2E)-3-(3-amino-5-fluoropyridin-2-yl)acrylate as a yellow solid.

[0135]To a suspension of 9.1 g of butyl
(2E)-3-(3-amino-5-fluoropyridin-2-yl)acrylate and 0.9 g of 10% palladium
carbon in 30 mL of methanol, 4 mL of formic acid was added, and 15 mL of
triethylamine was added dropwise thereto under ice cooling. The reaction
mixture was stirred at 60° C. for 2 hours. The reaction mixture
was cooled to room temperature, insoluble matter was filtered out, and
the filter residue was washed using 30 mL of toluene. The filtrate and
the wash liquid were combined and the solvent was evaporated under
reduced pressure. To the obtained residue, 30 mL of toluene was added,
the mixture was stirred at 100° C. for 2 hours and 30 minutes. To
the reaction mixture, 30 mL of water was added dropwise at 45° C.
and the mixture was cooled to 5° C. The solid product was obtained
by filtration and washed in the order of water and toluene to give 5.7 g
of 7-fluoro-3,4-dihydro-1,5-naphthyridin-2(1H)-one as a white solid.

[0139]To a suspension of 49.8 g of potassium phosphate in 90 mL dimethyl
sulfoxide, 30.0 g of 7-fluoro-3,4-dihydro-1,5-naphthyridin-2(1H)-one and
39.7 g of 2-bromo-1,1-dimethoxyethane were added, and the mixture was
stirred at 100° C. for 3 hours. To the mixture, 7.7 g of potassium
phosphate and 6.1 g of 2-bromo-1,1-dimethoxyethane were added, and the
mixture was stirred for 1 hour at the same temperature. The reaction
mixture was cooled to room temperature, and 120 mL of water and 120 mL of
toluene were added thereto. The mixture was adjusted to pH 8.5 with
acetic acid, and 3.0 g of activated carbon was added thereto. Insoluble
matter was filtered out, and the filter residue was washed using 30 mL of
toluene and 30 mL of water. The filtrate and the wash liquid were
combined, the organic layer was separated, and the aqueous layer was
extracted with 60 mL of toluene. The organic layer and the extract were
combined to evaporate the solvent under reduced pressure, 90 mL of
dibutyl ether was added thereto, and the mixture was cooled to -3°
C. The solid product was obtained by filtration and washed using in the
order of dibutyl ether and water to give 30.8 g of
1-(2,2-dimethoxyethyl)-7-fluoro-3,4-dihydro-1,5-naphthyridin-2(1H)-one as
a light yellow solid.

[0142]To a suspension of 5.0 g of
1-(2,2-dimethoxyethyl)-7-fluoro-3,4-dihydro-1,5-naphthyridin-2(1H)-one,
5.3 g of N-bromosuccinimide and 3.0 g of potassium carbonate in 30 mL of
chlorobenzene, 0.12 g of 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile)
was added three times hourly at 50 to 60° C. under a nitrogen
atmosphere. After stirring the reaction mixture for 1 hour at the same
temperature, 10 mL of water was added thereto, and the mixture was
adjusted to pH 12.6 using a 20% sodium hydroxide solution. The organic
layer was separated and washed with 15 mL of water. The aqueous layer was
extracted with 15 mL of toluene. The organic layer and the extract were
combined to evaporate the solvent under reduced pressure. To the obtained
residue, 2 mL of chlorobenzene and 6 mL of cyclohexane were added, the
mixture was stirred for 30 minutes under ice cooling, and the solid
product was obtained by filtration and washed with cyclohexane to give
4.1 g of 1-(2,2-dimethoxyethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one as a
light yellow solid.

[0146]To a suspension of 158 g of
1-(2,2-dimethoxyethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one in 1.26 L of
2-butanone, 79 mL of 12 mol/L hydrochloric acid was added at room
temperature, and the mixture was refluxed for 3 hours. After cooling the
reaction mixture to 10° C., the solid product was obtained by
filtration and washed with 2-butanone to give 152 g of
(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde hydrochloride
monohydrate as a light yellow solid.

[0149]To a suspension of 14.3 g of kojic acid in 57 mL of tetrahydrofuran,
11 mL of 3,4-dihydro-2H-pyran and 77 mg of p-toluenesulfonic acid
monohydrate were added, and the mixture was stirred for 6 hours at room
temperature. To the mixture, 1 mL of a 0.5 mol/L sodium hydroxide aqueous
solution was added, and the solvent was evaporated under reduced pressure
to give 26.8 g of
5-hydroxy-2-((tetrahydro-2H-pyran-2-yloxy)methyl)-4H-pyran-4-one as a
light yellow solid.

[0150]To a solution of the obtained
5-hydroxy-2-(tetrahydro-2H-pyran-2-yloxy)methyl)-4H-pyran-4-one in 45 mL
of N,N-dimethylformamide, 45 mL of toluene, 20.8 mL of
1-bromo-2-chloroethane and 41.6 g of potassium carbonate were added, and
the mixture was stirred for 4 hours at 60° C. The mixture was
allowed to stand overnight at room temperature, and the solvent was
evaporated under reduced pressure. To the obtained residue, 107 mL of
water and 90 mL of ethyl acetate-17 mL of toluene were added. The organic
layer was separated, and the aqueous layer was extracted using 90 mL of
ethyl acetate-17 mL of toluene. The organic layer and the extract were
combined and the solvent was evaporated under reduced pressure to give
26.7 g of 5-(2-chloroethoxy)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)-4H-p-
yran-4-one as a brown oily substance.

[0153]To a solution of 314 g of
5-(2-chloroethoxy)-2-((tetrahydro-2H-pyran-2-yloxy)methyl)-4H-pyran-4-one
in 630 mL of methanol, 6.3 mL of concentrated hydrochloric acid was added
and the mixture was stirred for 6 hours at room temperature. To the
reaction mixture, 13 mL of 28% ammonia water was added and the solvent
was evaporated under reduced pressure to give 240 g of
5-(2-chloroethoxy)-2-(hydroxymethyl)-4H-pyran-4-one (crude product) as a
brown oily substance.

[0158]To 229 g of 5-(2-chloroethoxy)-2-(hydroxymethyl)-4H-pyran-4-one
(crude product), 572 mL of 28% ammonia water was added, the mixture was
stirred for 7 hours at 85° C. and allowed to stand overnight at
room temperature. The reaction mixture was extracted 4 times with 500 mL
of 2-propyl acetate. The organic layer was combined therewith and the
solvent was evaporated under reduced pressure to give 90.5 g of
(2,3-dihydro-(1,4)dioxino(2,3-c)pyridin-7-yl)methanol as a brown oily
substance.

[0161]To a solution of 111 g of
(2,3-dihydro-(1,4)dioxino(2,3-c)pyridin-7-yl)methanol in 1110 mL of
tetrahydrofuran, 164 g of manganese dioxide was added, the mixture was
stirred for 5 hours at 70° C. and stirred overnight at room
temperature. The reaction mixture was subjected to celite filtration and
the filter residue was washed with 500 mL of tetrahydrofuran. The
filtrate and the wash liquid were combined to evaporate the solvent under
reduced pressure. The obtained residue was recrystallized from 750 mL of
2-propanol to give 53.5 g of
2,3-dihydro-(1,4)dioxino(2,3-c)pyridin-7-carbaldehyde as a light yellow
solid.

[0164]A solution of 3.0 g of
2,3-dihydro-(1,4)dioxino(2,3-c)pyridin-7-carbaldehyde and 3.4 g of
4-amino-1-benzylpiperidine in 30 mL of methanol was stirred for 50
minutes at room temperature, and a solution of 0.34 g of sodium
borohydride in 30 mL of 0.01 mol/L sodium hydroxide/methanol was added
dropwise thereto under ice cooling. The mixture was further stirred for 2
hours under ice cooling, 6 mL of concentrated hydrochloric acid was added
dropwise thereto at 10° C. or lower and stirred for 1 hour 30
minutes. The solid product was obtained by filtration to give 6.8 g of
1-benzyl-N-(2,3-dihydro-(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)piperidin-4-
-amine trihydrochloride as a white solid.

[0167]To a solution of 6.8 g of
1-benzyl-N-(2,3-dihydro-(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)piperidin-4-
-amine trihydrochloride in 20 mL of water-11 mL of tetrahydrofuran, 8 mL
of a 20% sodium hydroxide aqueous solution was added under ice cooling,
and subsequently 3.3 g of di-tert-butyl dicarbonate was added thereto.
The mixture was stirred for 8 hours at room temperature and 11 mL of
ethyl acetate was added thereto. The organic layer was separated and 5.1
g of silica gel (Chromatorex-NH, FUJI SILYSIA CHAMICAL LTD.) was added
thereto. The mixture was stirred for 1 hour at room temperature and
filtrated by passing through 2.6 g of silica gel (Silica gel 60N, KANTO
CHEMICAL CO., INC). For washing, 35 mL of ethyl acetate was used. The
filtrate and the wash liquid were combined and the solvent was evaporated
under reduced pressure to give 6.3 g of tert-butyl
(1-benzylpiperidin-4-yl)(2,3-dihydro-(1,4)dioxino(2,3-c)pyridin-7-ylmethy-
l)carbamate as a light yellow foam.

[0172]To a solution of 5.0 g of tert-butyl
(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(piperidin-4-yl)carbama-
te monohydrate in 40 mL of N-methyl-2-pyrrolidone, 3.5 g of
(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde hydrochloride
monohydrate was added, and the mixture was stirred for 1 hour at room
temperature. To the mixture, 4.3 g of sodium triacetoxyborohydride was
added dividedly in 5 portions over the period of 80 minutes under ice
cooling, and the mixture was stirred for 1 hour and 40 minutes under ice
cooling. After heating to room temperature, the mixture was added with 20
mL of water and adjusted to pH 11.5 with an aqueous solution of 20%
sodium hydroxide. To the mixture, 20 mL of N-methyl-2-pyrrolidone was
added at 70 to 80° C., and the mixture was stirred for 2 hours and
30 minutes at the same temperature. The reaction mixture was cooled to
room temperature and the solid product was obtained by filtration and
washed with water to give 6.5 g of tert-butyl
(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-fluoro-2-oxo-1-
,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a light brown
solid.

[0177]A solution of 3.03 g of tert-butyl
(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-fluoro-2-oxo-1-
,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate in 45 mL of
trifluoroacetic acid was stirred for 1 hour and 30 minutes at room
temperature. The reaction mixture was cooled with ice, added with 30 mL
of water and 30 mL of ethyl acetate, and adjusted to pH 10 with a 2 mol/L
sodium hydroxide aqueous solution. The organic layer was separated and
the aqueous layer was extracted 7 times with ethyl acetate. The organic
layer was combined therewith and the solvent was concentrated to 10 mL
under reduced pressure, whereby insoluble matter was filtered out. The
solvent was evaporated under reduced pressure, and the obtained residue
was purified by basic silica gel column chromatography [eluate;
chloroform:methanol=92:8], recrystallized from 3 mL of ethyl acetate to
give 0.611 g of
1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidi-
n-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one (anhydrate) as a light
yellow solid.

[0182]To a suspension of 0.30 g of tert-butyl
(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-fluoro-2-oxo-1-
,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate in 2 mL of
2-propanol, 0.23 mL of concentrated hydrochloric acid was added, and the
resultant mixture was stirred for 1 hour and 50 minutes under reflux with
heating. The reaction mixture was cooled to 5° C., and the solid
was obtained by filtration to give 0.28 g of
1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)piperidi-
n-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one trihydrochloride as a
light yellow solid.

[0185]To a suspension of 3.00 g of 7-fluoro-1,5-naphthyridin-2(1H)-one and
5.04 g of potassium phosphate in 12 mL of dimethyl sulfoxide, 4.68 g of
2-bromo-1,1-diethoxyethane was added at room temperature, and the
resultant mixture was stirred for 4.5 hours at 94° C. The reaction
mixture was cooled, and 21 mL of water and 12 mL of cyclopentyl methyl
ether were added thereto. The mixture was adjusted to pH 5.8 with 12
mol/L hydrochloric acid, subsequently the insoluble matter was filtered
out, and the filter residue was washed twice with 3 mL of cyclopentyl
methyl ether. The organic layers of the obtained filtrate and the wash
liquid were separated, and the solvent was evaporated under reduced
pressure. The obtained residue was purified by silica gel column
chromatography to give 3.11 g of
1-(2,2-diethoxyethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one as a light
yellow oily substance.

[0188]To 480 mL of 2-butanone, 30 mL of 12 mol/L hydrochloric acid was
added, the mixture was heated to 70° C. and a solution of 60 g of
1-(2,2-diethoxyethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one in 60 mL of
2-butanone was added dropwise, followed by reflux for 2 hours. After
cooling the reaction mixture to 25° C., the solid product was
obtained by filtration and washed with 2-butanone to give 50.3 g of
(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)acetaldehyde hydrochloride
monohydrate as a light yellow solid.

[0190]The 1-(2-(4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino-
)piperidin-1-yl)ethyl)-7-fluoro-1,5-naphthyridin-2(1H)-one monohydrate of
the present invention (1) has strong antibacterial activity and high
safety, (2) does not exhibit deliquescence or hygroscopicity, (3) is easy
to handle, (4) is produced using a solvent which is safe to human body,
(5) is produced under conditions with a little environmental burden, and
(6) can be mass produced, thereby being useful as a bulk pharmaceutical.